PROJECT SUMMARY Hearing loss (HL) is the most prevalent childhood sensory impairment, posing a risk for deficits in aural communication. Moreover, these deficits can persevere even after normal audibility returns, suggesting that developmental HL permanently impairs central synapse function which compromises auditory perception. In fact, transient HL in gerbils induces perceptual deficits that are well-correlated with reduced inhibitory synaptic strength in auditory cortex (ACx) (Caras & Sanes, 2015; Mowery et al. 2015, 2016). Furthermore, this deficit is due to loss of both GABAA and GABAB receptor-mediated inhibition. Therefore, this proposal explores a causal relationship between weakened inhibition and perceptual deficits. Our core hypothesis is that developmental hearing loss induces a reduction of both postsynaptic GABAA- and GABAB receptor-mediated inhibition within auditory cortex, thereby causing perceptual deficits. Three aims test predictions that emerge from this hypothesis: Aim 1 tests the prediction that GABAA- and GABAB receptor-mediated inhibitory postsynaptic potentials (IPSP) must each be rescued to regain normal inhibitory strength following HL. Gerbils will be reared with transient bilateral HL (earplugs) from postnatal (P) days 11-23, and receive daily injections of a GABAergic enhancer during this period. Animals will then be reared to adulthood (>P86) with normal hearing, and an optogenetic approach will be used to assess GABAA and GABAB IPSPs in brain slices. To assess off- target effects, both EPSPs and discharge properties will be measured. Comparisons will be made to vehicle- treated HL and control animals. Aim 2 tests the prediction that HL-induced inhibitory weakening is intrinsic to ACx pyramidal cells. Gerbils will be reared with HL from P11-23, and ACx layer 2/3 pyramidal cells will then be transfected with genes that encode GABA receptor subunits or trafficking proteins, each obtained from the newly available gerbil genome sequence. As in Aim 1, optogenetic assessment of IPSPs, EPSPs, and discharge properties will be obtained from adult ACx. Aim 3 tests the prediction that perceptual deficits can be restored by rescuing ACx synaptic inhibition. Gerbils will be reared with HL from P11-23 and receive either: daily injections an effective GABA enhancer (Aim 1), or ACx transfection with an effective vector (Aim 2). Animals will then be tested on an amplitude modulation (AM) detection task to obtain psychometric thresholds. To determine whether perception correlates with inhibitory strength, an optogenetic assessment of IPSPs will be obtained from the same animals. Innovations in this proposal are: (i) collaborations to sequence the gerbil genome and to equip vectors with gerbil-specific genes, (ii) a high throughput assay of adult ACx synapse function using optogenetics, and (iii) an emphasis on the role of GABAB receptors in developmental disorders. Together, the significance of this proposal is to identify and remediate a CNS mechanism that contributes to the perceptual deficits that attend childhood HL. If successful, the project will provide one explanation for the educational barriers that persist in children with HL that is separate from cochlear pathology.